Kinases have been a targeted therapy strategy in oncology for many years, and include numerous different kinase families. Kinases regulate a myriad of normal cellular processes, but also play a critical role in the development and progression of many types of cancer. Agents that inhibit one or more kinases have shown promise as treatments for many different kinds of cancer. Multikinase inhibitors are agents that target one or more kinases.
Among the commonly used multikinase inhibitors in cancer therapy are sorafenib, sunitinib, gefitinib, erlotinib, temsirolimus, capecitabine, gemcitabine, 5-fluorouracil, tegafur, emitefur, vinorelbine, liposome-encapsulated or continuous-infusion doxorubicin, floxuridine, cytarabine, methotrexate, palifermin, docetaxel, cisplatin, clofarabine, cyclophosphamide, daunorubicin, etoposide, fluorouracil, hydroxyurea, 6-mercaptopurine, paclitaxel, 6-thioguanine, and troxacitabine.
A side of effect of treatment with multikinase inhibitors is the presentation of dermatologic toxicities that can manifest on many areas of the body, and in particular, the hands and feet, as well as on the face, cheeks, and back of patients; toxicities also present on the nails and affect hair follicles are hair growth. The dermatologic toxicities can include hand-foot syndrome, acneiform rashes such as papulopustular rashes, as well as psoriasis, pruritus, paronychia, and changes in hair growth. Patients may also develop various other skin rashes, and problems relating to the eyelids and eyelashes. Hand and foot blisters are often associated with multikinase inhibitor treatment. Because hand and foot surfaces are under pressure from walking and other activity, the skin in these areas is more sensitive, and pressure points can develop to contribute to the blisters and erythema.
These dermatologic toxicities can begin to manifest soon after multikinase inhibitor treatment or up to several months following the end of treatment. In some circumstances, conditions such as psoriasis can develop after, for example, the papulopustular rash has resolved.
The severity of the toxicities can vary throughout treatment, and can depend on the specific multikinase inhibitor used, and can even resolve, temporarily, throughout the duration of treatment. Once treatment discontinues, however, these toxicities can disappear.
Patients often discontinue multikinase inhibitor treatment as a result of the side effects. Frequently, therefore, physicians lower the multikinase inhibitor dosage to decrease the scale of the side effects, and in many cases, treatment is delayed as a result.
Importantly, there is a positive correlation between the severity of the dermatologic toxicities and how effective a multikinase inhibitor is in treating a patient's cancer. Studies demonstrate this positive correlation between development of the rash or other skin eruption, and clinical outcomes, including the extent to which, for example, a patient's tumor shrinks. Therefore, a means of preventing and/or treating side effects that might hinder the administration of multikinase inhibitors is crucial.
Many treatments to manage multikinase inhibitor side effects on the skin and related areas have been attempted, including the use of tetracycline, mild cleansers, hydrocortisone, clindamycin gel, and tacrolimus cream, as well as sunscreen and analgesics. These agents have proved largely unsuccessful in treating the toxic side effects of multikinase inhibitor treatment, and therefore there is a need for additional therapies that are efficacious in preventing and treating these unpleasant side effects.